The invention describes novel substituted aryl compounds that are cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or, optionally, at least one therapeutic agent. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity or other toxicities; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.
Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely used for the treatment of pain, inflammation, and acute and chronic inflammatory disorders such as osteoarthritis and rheumatoid arthritis. These compounds inhibit the activity of the enzyme cyclooxygenase (COX), also known as prostaglandin G/H synthase, which is the enzyme that converts arachidonic acid into prostanoids. The NSAIDs also inhibit the production of other prostaglandins, especially prostaglandin G2, prostaglandin H2 and prostaglandin E2, thereby reducing the prostaglandin-induced pain and swelling associated with the inflammation process. The chronic use of NSAIDs has been associated with adverse effects, such as gastrointestinal ulceration and renal toxicity. The undesirable side effects are also due to the inhibition of prostaglandin in the affected organ.
Recently two isoforms of cyclooxygenase, encoded by two distinct genes (Kujubu et al, J. Biol. Chem., 266, 12866-12872 (1991)), have been identifiedxe2x80x94a constitutive form, cyclooxygenase-1 (COX-1), and an inductive form, cyclooxygenase-2 (COX-2). It is thought that the antiinflammatory effects of NSAIDs are mediated by the inhibition of COX-2, whereas the side effects seem to be caused by the inhibition of COX-1. The NSAIDs currently on the market either inhibit both isoforms of COX with little selectivity for either isoform or are COX-1 selective. Recently compounds that are COX-2 selective inhibitors have been developed and marketed. These COX-2 selective inhibitors have the desired therapeutic profile of an antiinflammatory drug without the adverse effects commonly associated with the inhibition of COX-1. However, these compounds can result in dyspepsia and can cause gastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)). Additionally the COX-2 selective inhibitors can increase the risk of cardiovascular events in a patient (Mukherjee et al., JAMA 286(8) 954-959 (2001)); Hennan et al., Circulation, 104:820-825 (2001)).
There is still a need in the art for novel COX-2 selective inhibitor compounds that have gastroprotective properties, facilitate wound healing, decreased renal toxicity and dyspepsia, improved cardiovascular profile and that can be used at low dosages. The invention is directed to these, as well as other, important ends.
The invention provides novel aryl substituted compounds that are COX-2 selective inhibitors. These compounds are potent analgesics, have antiinflammatory properties and have an unexpected potential for facilitating wound healing. The novel compounds also have unexpected properties in the treatment and/or prevention of renal toxicity and for improving the cardiovascular profile of COX-2 selective inhibitors. The invention also provides compositions comprising the novel compounds described herein in a pharmaceutically acceptable carrier. The invention is also based on the discovery that administering at least one COX-2 selective inhibitor, and, optionally, at least one nitric oxide donor reduces the gastrointestinal distress induced by COX-2 selective inhibitors. A nitric oxide donor is a compound that contains a nitric oxide moiety and which releases or chemically transfers nitric oxide to another molecule. Nitric oxide donors include, for example, S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines, SPM 3672, SPM 5185, SPM 5186 and analogues thereof, and substrates of the various isozymes of nitric oxide synthase. Thus, another aspect of the invention provides compositions comprising at least one COX-2 selective inhibitor, and at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxc2x7), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase.
Yet another aspect of the invention provides compositions comprising at least one COX-2 selective inhibitor that is substituted with at least one nitrogen monoxide group (NO), and/or at least one nitrogen dioxide group (NO2) (i.e., nitrosylated and/or nitrosated). The COX-2 selective inhibitors can be nitrosated and/or nitrosylated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen. The invention also provides compositions comprising a therapeutically effective amount of such compounds in a pharmaceutically acceptable carrier.
Another aspect of the invention provides compositions comprising a therapeutically effective amount of at least one COX-2 selective inhibitor that is substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), and at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxc2x7), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The invention also provides for such compositions in a pharmaceutically acceptable carrier.
Yet another aspect of the invention provides compositions comprising at least one COX-2 selective inhibitor, that is optionally substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), and, optionally, at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxc2x7), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase, and/or, optionally, at least one therapeutic agent, including but not limited to, steroids, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and the like.
Yet another aspect of the invention provides methods for treating and/or preventing inflammation, pain and fever; for treating and/or improving gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity; and for treating and/or preventing COX-2 mediated disorders (i.e., disorders resulting from elevated levels of COX-2) in a patient in need thereof which comprises administering to the patient a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), and, optionally, at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxc2x7), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase and/or stimulates endogenous production of NO or EDRF in vivo and/or is a substrate for nitric oxide synthase (i.e. NO donor). The methods can optionally further comprise the administration of at least one therapeutic agent, such as, for example, steroids, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. In this aspect of the invention, the methods can involve administering the COX-2 selective inhibitors, that are optionally nitrosated and/or nitrosylated, administering the COX-2 selective inhibitors, that are optionally nitrosated and/or nitrosylated, and NO donors, administering the COX-2 selective inhibitors, that are optionally nitrosated and/or nitrosylated, and therapeutic agents, or administering the COX-2 selective inhibitors, that are optionally nitrosated and/or nitrosylated, NO donors, and therapeutic agents.
Yet another aspect of the invention provides methods for improving the cardiovascular profile of COX-2 selective inhibitors in a patient in need thereof which comprises administering to the patient a therapeutically effective amount of at least one COX-2 selective inhibitor, substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), and, optionally, at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxc2x7), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase and/or stimulates endogenous production of NO or EDRF in vivo and/or is a substrate for nitric oxide synthase (i.e. NO donor). The methods can optionally further comprise the administration of at least one of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, and mixtures thereof. In this aspect of the invention, the methods can involve administering the nitrosated and/or nitrosylated COX-2 selective inhibitors, administering the COX-2 selective inhibitors, that are optionally nitrosated and/or nitrosylated, and NO donors, administering the COX-2 selective inhibitors, that are optionally nitrosated and/or nitrosylated, and at least one of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, antiplatelet agents, thrombin inhibitors or thromboxane inhibitors, or administering the COX-2 selective inhibitors, that are optionally nitrosated and/or nitrosylated, NO donors, and at least one of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, antiplatelet agents, thrombin inhibitors or thromboxane inhibitors.
In yet another aspect the invention provides kits comprising at least one COX-2 selective inhibitor, that is optionally substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), and, optionally, at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxc2x7), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The kit can further comprise at least one therapeutic agent, such as, for example, steroids, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. The COX-2 selective inhibitor, the nitric oxide donor and/or therapeutic agent, can be separate components in the kit or can be in the form of a composition in one or more pharmaceutically acceptable carriers.
As used throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
xe2x80x9cNSAIDxe2x80x9d refers to a nonsteroidal anti-inflammatory compound or a nonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, the enzyme responsible for the biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of the various isozymes of cyclooxygenase (including but not limited to cyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase and lipoxygenase.
xe2x80x9cCyclooxygenase-2 (COX-2) selective inhibitorxe2x80x9d refers to a compound that selectively inhibits the cyclooxygenase-2 enzyme over the cyclooxygenase-1 enzyme. In one embodiment, the compound has a cyclooxygenase-2 IC50 of less than about 2 xcexcM and a cyclooxygenase-1 IC50 of greater than about 5 xcexcM, in the human whole blood COX-2 assay (as described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) and also has a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 10, and preferably of at least 40. In another embodiment, the compound has a cyclooxygenase-1 IC50 of greater than about 1 xcexcM, and preferably of greater than 20 xcexcM. The compound can also inhibit the enzyme, lipoxygenase. Such selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
xe2x80x9cTherapeutic agentxe2x80x9d includes any therapeutic agent that can be used to treat or prevent the diseases described herein. xe2x80x9cTherapeutic agentsxe2x80x9d include, for example, steroids, nonsteroidal antiinflammatory compounds, 5-lipoxygenase inhibitors, leukotriene B4 receptor antagonists, leukotriene A4 hydrolase inhibitors, 3-hydroxy-3-methylglutaryl coenzyme A inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and the like. Although NO donors have therapeutic activity, the term xe2x80x9ctherapeutic agentxe2x80x9d does not include NO donors described herein, since NO donors are separately defined.
xe2x80x9cCardiovascular disease or disorderxe2x80x9d refers to any cardiovascular disease or disorder known in the art, including, but not limited to, restenosis, atherosclerosis, atherogenesis, angina, (particularly chronic, stable angina pectoris), ischemic disease, congestive heart failure or pulmonary edema associated with acute myocardial infarction, thrombosis, controlling blood pressure in hypertension (especially hypertension associated with cardiovascular surgical procedures), thromboemboembolic events, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, vascular complications associated with the use of medical devices, wounds associated with the use of medical devices, cerebrovascular ischemic events, and the like. Complications associated with the use of medical devices may occur as a result of increased platelet deposition, activation, thrombus formation or consumption of platelets and coagulation proteins. Such complications, which are within the definition of xe2x80x9ccardiovascular disease or disorder,xe2x80x9d include, for example, myocardial infarction, ischemic stroke, transient ischemic stroke, thromboemboembolic events, pulmonary thromboembolism, cerebral thromboembolism, thrombophlebitis, thrombocytopenia, bleeding disorders and/or any other complications which occur either directly or indirectly as a result of the foregoing disorders.
xe2x80x9cRestenosisxe2x80x9d is a cardiovascular disease or disorder that refers to the closure of a peripheral or coronary artery following trauma to the artery caused by an injury such as, for example, angioplasty, balloon dilation, atherectomy, laser ablation treatment or stent insertion. For these angioplasty procedures, restenosis occurs at a rate of about 30-60% depending upon the vessel location, lesion length and a number of other variables. Restenosis can also occur following a number of invasive surgical techniques, such as, for example, transplant surgery, vein grafting, coronary artery bypass surgery, endarterectomy, heart transplantation, balloon angioplasty, atherectomy, laser ablation, endovascular stenting, and the like.
xe2x80x9cAtherosclerosisxe2x80x9d is a form of chronic vascular injury in which some of the normal vascular smooth muscle cells in the artery wall, which ordinarily control vascular tone regulating blood flow, change their nature and develop xe2x80x9ccancer-likexe2x80x9d behavior. These vascular smooth muscle cells become abnormally proliferative, secreting substances such as growth factors, tissue-degradation enzymes and other proteins, which enable them to invade and spread into the inner vessel lining, blocking blood flow and making that vessel abnormally susceptible to being completely blocked by local blood clotting, resulting in the death of the tissue served by that artery. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all common manifestations of atherosclerosis and are therefore encompassed by the terms xe2x80x9catherosclerosisxe2x80x9d and xe2x80x9catherosclerotic diseasexe2x80x9d.
xe2x80x9cImproving the cardiovascular profilexe2x80x9d refers to and includes reducing the risk of thromboembolic events, reducing the risk of developing atherosclerosis and atherosclerotic diseases, and inhibiting platelet aggregation.
xe2x80x9cThromboemboembolic eventsxe2x80x9d includes, but is not limited to, ischemic stroke, transient ischemic stroke, myocardial infarction, angina pectoris, thrombosis, thromboembolism, thrombotic occlusion and reocclusion, acute vascular events, restenosis, transient ischemic attacks, and first and subsequent thrombotic stroke. Patients who are at risk of developing thromboembolic events, may include those with a familial history of, or genetically predisposed to, thromboembolic disorders, who have had ischemic stroke, transient ischemic stroke, myocardial infarction, and those with unstable angina pectoris or chronic stable angina pectoris and patients with altered prostacyclin/thromboxane A2 homeostasis or higher than normal thromboxane A2 levels leading to increase risk for thromboembolism, including patients with diabetes and rheumatoid arthritis.
xe2x80x9cThromboxane inhibitorxe2x80x9d refers to any compound that reversibly or irreversibly inhibits thromboxane synthesis, and includes compounds which are the so-called thromboxane A2 receptor antagonists, thromboxane A2 antagonists, thromboxane A2/prostaglandin endoperoxide antagonists, thromboxane receptor (TP) antagonists, thromboxane antagonists, thromboxane synthase inhibitors, and dual acting thromboxane synthase inhibitors and thromboxane receptor antagonists. The characteristics of the preferred thromboxane inhibitor should include the suppression of thromboxane A2 formation (thromboxane synthase inhibitors) and/or blockade of thromboxane A2 and prostaglandin H2 platelet and vessel wall (thromboxane receptor antagonists). The effects should block platelet activation and therefore platelet function.
xe2x80x9cThromboxane A2 receptor antagonistxe2x80x9d refers to any compound that reversibly or irreversibly blocks the activation of any thromboxane A2 receptor.
xe2x80x9cThromboxane synthase inhibitorxe2x80x9d refers to any compound that reversibly or irreversibly inhibits the enzyme thromboxane synthesis thereby reducing the formation of thromboxane A2. Thromboxane synthase inhibitors may also increase the synthesis of antiaggregatory prostaglandins including prostacyclin and prostaglandin D2. Thromboxane A2 receptor antagonists and thromboxane synthase inhibitors and can be identified using the assays described in Tai, Methods of Enzymology, Vol. 86, 110-113 (1982); Hall, Medicinal Research Reviews, 11:503-579 (1991) and Coleman et al., Pharmacol Rev., 46: 205-229 (1994) and references therein, the disclosures of which are incorporated herein by reference in its entirety.
xe2x80x9cDual acting thromboxane receptor antagonist and thromboxane synthase inhibitorxe2x80x9d refers to any compound that simultaneously acts as a thromboxane A2 receptor antagonist and a thromboxane synthase inhibitor.
xe2x80x9cThrombin inhibitorsxe2x80x9d refers to and includes compounds that inhibit hydrolytic activity of thrombin, including the catalytic conversion of fibrinogen to fibrin, activation of Factor V to Va, Factor VIII to VIIIa, Factor XIII to XIIIa and platelet activation. Thrombin inhibitors may be identified using assays described in Lewis et at., Thrombosis Research. 70: 173-190 (1993).
xe2x80x9cPlatelet aggregationxe2x80x9d refers to the binding of one or more platelets to each other. Platelet aggregation is commonly referred to in the context of generalized atherosclerosis, not with respect to platelet adhesion on vasculature damaged as a result of physical injury during a medical procedure. Platelet aggregation requires platelet activation which depends on the interaction between the ligand and its specific platelet surface receptor.
xe2x80x9cPlatelet activationxe2x80x9d refers either to the change in conformation (shape) of a cell, expression of cell surface proteins (e.g., the IIb/IIIa receptor complex, loss of GPIb surface protein), and secretion of platelet derived factors (e.g., serotonin, growth factors).
xe2x80x9cPatientxe2x80x9d refers to animals, preferably mammals, most preferably humans, and includes males and females, and children and adults.
xe2x80x9cTherapeutically effective amountxe2x80x9d refers to the amount of the compound and/or composition that is effective to achieve its intended purpose.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d refers to and includes alleviating, ameliorating, relieving or otherwise reducing the signs and symptoms associated with a disease or disorder.
xe2x80x9cPreventingxe2x80x9d or xe2x80x9cpreventionxe2x80x9d refers to and includes prophylaxis or delaying the onset or progression of a disease or disorders, or the signs and symptoms associated with such disease or disorder.
xe2x80x9cTransdermalxe2x80x9d refers to the delivery of a compound by passage through the skin and into the blood stream.
xe2x80x9cTransdermalxe2x80x9d refers to delivery of a compound by passage of the compound through the mucosal tissue and into the blood stream.
xe2x80x9cPenetration enhancementxe2x80x9d or xe2x80x9cpermeation enhancementxe2x80x9d refers to an increase in the permeability of the skin or mucosal tissue to a selected pharmacologically active compound such that the rate at which the compound permeates through the skin or mucosal tissue is increased.
xe2x80x9cCarriersxe2x80x9d or xe2x80x9cvehiclesxe2x80x9d refers to carrier materials suitable for compound administration and include any such material known in the art such as, for example, any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is non-toxic and which does not interact with any components of the composition in a deleterious manner.
xe2x80x9cNitric oxide adductxe2x80x9d or xe2x80x9cNO adductxe2x80x9d refers to compounds and functional groups which, under physiological conditions, can donate, release and/or directly or indirectly transfer any of the three redox forms of nitrogen monoxide (NO+, NOxe2x88x92, NOxc2x7), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
xe2x80x9cNitric oxide releasingxe2x80x9d or xe2x80x9cnitric oxide donatingxe2x80x9d refers to methods of donating, releasing and/or directly or indirectly transferring any of the three redox forms of nitrogen monoxide (NO+, NOxe2x88x92, NOxc2x7), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
xe2x80x9cNitric oxide donorxe2x80x9d or xe2x80x9cNO donorxe2x80x9d refers to compounds that donate, release and/or directly or indirectly transfer a nitrogen monoxide species, and/or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo. xe2x80x9cNO donorxe2x80x9d also includes compounds that are substrates for nitric oxide synthase.
xe2x80x9cAlkylxe2x80x9d refers to a lower alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein. An alkyl group may also comprise one or more radical species, such as, for example a cycloalkylalkyl group or a heterocyclicalkyl group.
xe2x80x9cLower alkylxe2x80x9d refers to branched or straight chain acyclic alkyl group comprising one to about ten carbon atoms (preferably one to about eight carbon atoms, more preferably one to about six carbon atoms). Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the like.
xe2x80x9cSubstituted lower alkylxe2x80x9d refers to a lower alkyl group, as defined herein, wherein one or more of the hydrogen atoms have been replaced with one or more R100 groups, wherein each R100 is independently a hydroxy, an oxo, a carboxyl, a carboxamido, a halo, a cyano or an amino group, as defined herein.
xe2x80x9cHaloalkylxe2x80x9d refers to a lower alkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein, to which is appended one or more halogens, as defined herein. Exemplary haloalkyl groups include trifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and the like.
xe2x80x9cAlkenylxe2x80x9d refers to a branched or straight chain C2-C10 hydrocarbon (preferably a C2-C8 hydrocarbon, more preferably a C2-C6 hydrocarbon) that can comprise one or more carbon-carbon double bonds. Exemplary alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbutene-1-yl, 3-methylbuten-1-yl, hexan-1-yl, hepten-1-yl, octen-1-yl, and the like.
xe2x80x9cLower alkenylxe2x80x9d refers to a branched or straight chain C2-C4 hydrocarbon that can comprise one or two carbon-carbon double bonds.
xe2x80x9cSubstituted alkenylxe2x80x9d refers to a branched or straight chain C2-C10 hydrocarbon (preferably a C2-C8 hydrocarbon, more preferably a C2-C6 hydrocarbon) which can comprise one or more carbon-carbon double bonds, wherein one or more of the hydrogen atoms have been replaced with one or more R100 groups, wherein each R100 is independently a hydroxy, an oxo, a carboxyl, a carboxamido, a halo, a cyano or an amino group, as defined herein.
xe2x80x9cAlkynylxe2x80x9d refers to an unsaturated acyclic C2-C10 hydrocarbon (preferably a C2-C8 hydrocarbon, more preferably a C2-C6 hydrocarbon) that can comprise one or more carbon-carbon triple bonds. Exemplary alkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl, hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.
xe2x80x9cBridged cycloalkylxe2x80x9d refers to two or more cycloalkyl groups, heterocyclic groups, or a combination thereof fused via adjacent or non-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridged cycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl, 2,6-dioxabicyclo(3.3.0)octane, 7-oxabycyclo(2.2.1)heptyl, 8-azabicyclo(3,2,1)oct-2-enyl and the like.
xe2x80x9cCycloalkylxe2x80x9d refers to a saturated or unsaturated cyclic hydrocarbon comprising from about 3 to about 10 carbon atoms. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo, alkylsulfinyl, and nitro. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like.
xe2x80x9cHeterocyclic ring or groupxe2x80x9d refers to a saturated or unsaturated cyclic hydrocarbon group having about 2 to about 10 carbon atoms (preferably about 4 to about 6 carbon atoms) where 1 to about 4 carbon atoms are replaced by one or more nitrogen, oxygen and/or sulfur atoms. Sulfur maybe in the thio, sulfinyl or sulfonyl oxidation state. The heterocyclic ring or group can be fused to an aromatic hydrocarbon group. Heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester, alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido, alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester, sulfonamido and nitro. Exemplary heterocyclic groups include pyrrolyl, furyl, thienyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, tetrazolyl, pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, imidazolinyl, imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, benzothiazolinyl, quinolinyl, and the like.
xe2x80x9cHeterocyclic compoundsxe2x80x9d refer to mono- and polycyclic compounds comprising at least one aryl or heterocyclic ring.
xe2x80x9cArylxe2x80x9d refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or two aromatic rings. Exemplary aryl groups include phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino, aryl amino, diarylamino, alkylarylamino, halo, cyano, alkylsulfinyl, hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamido and nitro. Exemplary substituted aryl groups include tetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfonyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d refers to an unsaturated cyclic C2-C10 hydrocarbon (preferably a C2-C8 hydrocarbon, more preferably a C2-C6 hydrocarbon) which can comprise one or more carbon-carbon triple bonds.
xe2x80x9cArylalkylxe2x80x9d refers to an aryl radical, as defined herein, attached to an alkyl radical, as defined herein. Exemplary arylalkyl groups include benzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl, 2-fluorophenylethyl, and the like.
xe2x80x9cArylalkenylxe2x80x9d refers to an aryl radical, as defined herein, attached to an alkenyl radical, as defined herein. Exemplary arylalkenyl groups include styryl, propenylphenyl, and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d refers to a cycloalkyl radical, as defined herein, attached to an alkyl radical, as defined herein.
xe2x80x9cCycloalkylalkoxyxe2x80x9d refers to a cycloalkyl radical, as defined herein, attached to an alkoxy radical, as defined herein.
xe2x80x9cCycloalkylalkylthioxe2x80x9d refers to a cycloalkyl radical, as defined herein, attached to an alkylthio radical, as defined herein.
xe2x80x9cHeterocyclicalkylxe2x80x9d refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein.
xe2x80x9cArylheterocyclic ringxe2x80x9d refers to a bi- or tricyclic ring comprised of an aryl ring, as defined herein, appended via two adjacent carbon atoms of the aryl ring to a heterocyclic ring, as defined herein. Exemplary arylheterocyclic rings include dihydroindole, 1,2,3,4-tetra-hydroquinoline, and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to R50Oxe2x80x94, wherein R50 is an alkyl group, as defined herein (preferably a lower alkyl group or a haloalkyl group, as defined herein). Exemplary alkoxy groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, trifluoromethoxy, and the like.
xe2x80x9cLower alkoxyxe2x80x9d refers to a lower alkyl group, as defined herein, appended to an oxygen atom.
xe2x80x9cAryloxyxe2x80x9d refers to R55Oxe2x80x94, wherein R55 is an aryl group, as defined herein. Exemplary arylkoxy groups include napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like.
xe2x80x9cAlkylthioxe2x80x9d refers to R50Sxe2x80x94, wherein R50 is an alkyl group, as defined herein.
xe2x80x9cLower alkylthioxe2x80x9d refers to a lower alkyl group, as defined herein, appended to a thio group, as defined herein.
xe2x80x9cArylalkoxyxe2x80x9d or xe2x80x9calkoxyarylxe2x80x9d refers to an alkoxy group, as defined herein, to which is appended an aryl group, as defined herein. Exemplary arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy, and the like.
xe2x80x9cAlkoxyalkylxe2x80x9d refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined herein. Exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.
xe2x80x9cAlkoxyhaloalkylxe2x80x9d refers to an alkoxy group, as defined herein, appended to a haloalkyl group, as defined herein. Exemplary alkoxyhaloalkyl groups include 4-methoxy-2-chlorobutyl and the like.
xe2x80x9cCycloalkoxyxe2x80x9d refers to R54Oxe2x80x94, wherein R54 is a cycloalkyl group or a bridged cycloalkyl group, as defined herein. Exemplary cycloalkoxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
xe2x80x9cCycloalkylthioxe2x80x9d refers to R54Sxe2x80x94, wherein R54 is a cycloalkyl group or a bridged cycloalkyl group, as defined herein. Exemplary cycloalkylthio groups include cyclopropylthio, cyclopentylthio, cyclohexylthio, and the like.
xe2x80x9cHaloalkoxyxe2x80x9d refers to an alkoxy group, as defined herein, in which one or more of the hydrogen atoms on the alkoxy group are substituted with halogens, as defined herein.
Exemplary haloalkoxy groups include 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.
xe2x80x9cHydroxyxe2x80x9d refers to xe2x80x94OH.
xe2x80x9cOxoxe2x80x9d refers to xe2x95x90O.
xe2x80x9cOxyxe2x80x9d refers to xe2x80x94Oxe2x88x92 R77+ wherein R77 is an organic or inorganic cation.
xe2x80x9cOrganic cationxe2x80x9d refers to a positively charged organic ion. Exemplary organic cations include alkyl substituted ammonium cations, and the like.
xe2x80x9cInorganic cationxe2x80x9d refers to a positively charged metal ion. Exemplary inorganic cations include Group I metal cations such as for example, sodium, potassium, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d refers to a hydroxy group, as defined herein, appended to an alkyl group, as defined herein.
xe2x80x9cNitratexe2x80x9d refers to xe2x80x94Oxe2x80x94NO2.
xe2x80x9cNitritexe2x80x9d refers to xe2x80x94Oxe2x80x94NO.
xe2x80x9cThionitratexe2x80x9d refers to xe2x80x94Sxe2x80x94NO2.
xe2x80x9cThionitritexe2x80x9d and xe2x80x9cnitrosothiolxe2x80x9d refer to xe2x80x94Sxe2x80x94NO.
xe2x80x9cNitroxe2x80x9d refers to the group xe2x80x94NO2 and xe2x80x9cnitrosatedxe2x80x9d refers to compounds that have been substituted therewith.
xe2x80x9cNitrosoxe2x80x9d refers to the group xe2x80x94NO and xe2x80x9cnitrosylatedxe2x80x9d refers to compounds that have been substituted therewith.
xe2x80x9cNitrilexe2x80x9d and xe2x80x9ccyanoxe2x80x9d refer to xe2x80x94CN.
xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to iodine (I), bromine (Br), chlorine (Cl), and/or fluorine (F).
xe2x80x9cAminoxe2x80x9d refers to xe2x80x94NH2, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein.
xe2x80x9cAlkylaminoxe2x80x9d refers to R50NHxe2x80x94, wherein R50 is an alkyl group, as defined herein. Exemplary alkylamino groups include methylamino, ethylamino, butylamino, cyclohexylamino, and the like.
xe2x80x9cArylaminoxe2x80x9d refers to R55NHxe2x80x94, wherein R55 is an aryl group, as defined herein.
xe2x80x9cDialkylaminoxe2x80x9d refers to R52R53Nxe2x80x94, wherein R52 and R53 are each independently an alkyl group, as defined herein. Exemplary dialkylamino groups include dimethylamino, diethylamino, methyl propargylamino, and the like.
xe2x80x9cDiarylaminoxe2x80x9d refers to R55R60Nxe2x80x94, wherein R55 and R60 are each independently an aryl group, as defined herein.
xe2x80x9cAlkylarylamino or arylalkylaminoxe2x80x9d refers to R52R55Nxe2x80x94, wherein R52 is an alkyl group, as defined herein, and R55 is an aryl group, as defined herein.
xe2x80x9cAlkylarylalkylaminoxe2x80x9d refers to R52R79Nxe2x80x94, wherein R52 is an alkyl group, as defined herein, and R79 is in arylalkyl group, as defined herein.
xe2x80x9cAlkylcycloalkylaminoxe2x80x9d refers to R52R80Nxe2x80x94, wherein R52 is an alkyl group, as defined herein, and R80 is in cycloalkyl group, as defined herein.
xe2x80x9cAminoalkylxe2x80x9d refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an alkyl group, as defined herein. Exemplary aminoalkyl groups include dimethylaminopropyl, diphenylaminocyclopentyl, methylaminomethyl, and the like.
xe2x80x9cAminoarylxe2x80x9d refers to an aryl group to which is appended an alkylamino group, a arylamino group or an arylalkylamino group. Exemplary aminoaryl groups include anilino, N-methylanilino, N-benzylanilino, and the like.
xe2x80x9cThioxe2x80x9d refers to xe2x80x94Sxe2x80x94.
xe2x80x9cSulfinylxe2x80x9d refers to xe2x80x94S(O)xe2x80x94.
xe2x80x9cMethanthialxe2x80x9d refers to xe2x80x94C(S)xe2x80x94.
xe2x80x9cThialxe2x80x9d refers to xe2x95x90S.
xe2x80x9cSulfonylxe2x80x9d refers to xe2x80x94S(O)2xe2x88x92.
xe2x80x9cSulfonic acidxe2x80x9d refers to xe2x80x94S(O)2OR76, wherein R76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
xe2x80x9cAlkylsulfonic acidxe2x80x9d refers to a sulfonic acid group, as defined herein, appended to an alkyl group, as defined herein.
xe2x80x9cArylsulfonic acidxe2x80x9d refers to a sulfonic acid group, as defined herein, appended to an aryl group, as defined herein.
xe2x80x9cSulfonic esterxe2x80x9d refers to xe2x80x94S(O)2OR58, wherein R58 is an alkyl group, an aryl group, or an aryl heterocyclic ring, as defined herein.
xe2x80x9cSulfonamidoxe2x80x9d refers to xe2x80x94S(O)2xe2x80x94N(R51)(R57), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, is defined herein.
xe2x80x9cAlkylsulfonamidoxe2x80x9d refers to a sulfonamido group, as defined herein, appended to an alkyl group, as defined herein.
xe2x80x9cArylsulfonamidoxe2x80x9d refers to a sulfonamido group, as defined herein, appended to an aryl group, as defined herein.
xe2x80x9cAlkylthioxe2x80x9d refers to R50Sxe2x80x94, wherein R50 is an alkyl group, as defined herein (preferably a lower alkyl group, as defined herein).
xe2x80x9cArylthioxe2x80x9d refers to R55Sxe2x80x94, wherein R55 is an aryl group, as defined herein.
xe2x80x9cArylalkylthioxe2x80x9d refers to an aryl group, as defined herein, appended to an alkylthio group, as defined herein.
xe2x80x9cAlkylsulfinylxe2x80x9d refers to R50xe2x80x94S(O)xe2x80x94, wherein R50 is an alkyl group, as defined herein.
xe2x80x9cAlkylsulfonylxe2x80x9d refers to R50xe2x80x94S(O)2xe2x80x94, wherein R50 is an alkyl group, as defined herein.
xe2x80x9cAlkylsulfonyloxyxe2x80x9d refers to R50xe2x80x94S(O)2xe2x80x94Oxe2x80x94, wherein R50 is an alkyl group, as defined herein.
xe2x80x9cArylsulfinylxe2x80x9d refers to R55xe2x80x94S(O)xe2x80x94, wherein R55 is an aryl group, as defined herein.
xe2x80x9cArylsulfonylxe2x80x9d refers to R55xe2x80x94S(O)2xe2x80x94, wherein R55 is an aryl group, as defined herein.
xe2x80x9cArylsulfonyloxyxe2x80x9d refers to R55xe2x80x94S(O)2xe2x80x94Oxe2x80x94, wherein R55 is an aryl group, as defined herein.
xe2x80x9cAmidylxe2x80x9d refers to R51C(O)N(R57)xe2x80x94 wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
xe2x80x9cEsterxe2x80x9d refers to R51C(O)Oxe2x80x94 wherein R51 is a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein.
xe2x80x9cCarbamoylxe2x80x9d refers to xe2x80x94Oxe2x80x94C(O)N(R51)(R57), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
xe2x80x9cCarboxylxe2x80x9d refers to xe2x80x94C(O)OR76, wherein R76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
xe2x80x9cCarbonylxe2x80x9d refers to xe2x80x94C(O)xe2x80x94.
xe2x80x9cAlkylcarbonylxe2x80x9d refers to R52xe2x80x94C(O)xe2x80x94, wherein R52 is an alkyl group, as defined herein.
xe2x80x9cArylcarbonylxe2x80x9d refers to R55xe2x80x94C(O)xe2x80x94, wherein R55 is an aryl group, as defined herein.
xe2x80x9cArylalkycarbonylxe2x80x9d refers to R55xe2x80x94R52xe2x80x94C(O)xe2x80x94, wherein R55 is an aryl group, as defined herein, and R52 is an alkyl group, as defined herein.
xe2x80x9cAlkylarylicarbonylxe2x80x9d refers to R52xe2x80x94R55xe2x80x94C(O)xe2x80x94, wherein R55 is an aryl group, as defined herein, and R52 is an alkyl group, as defined herein.
xe2x80x9cHeterocyclicalkylcarbonylxe2x80x9d refer to R78C(O)xe2x80x94 wherein R78 is a heterocyclicalkyl group, as defined herein.
xe2x80x9cCarboxylic esterxe2x80x9d refers to xe2x80x94C(O)OR58, wherein R58 is an alkyl group, an aryl group or an aryl heterocyclic ring, as defined herein.
xe2x80x9cAlkylcarboxylic acidxe2x80x9d and xe2x80x9calkylcarboxylxe2x80x9d refer to an alkyl group, as defined herein, appended to a carboxyl group, as defined herein.
xe2x80x9cAlkylcarboxylic esterxe2x80x9d refers to an alkyl group, as defined herein, appended to a carboxylic ester group, as defined herein.
xe2x80x9cArylcarboxylic acidxe2x80x9d refers to an aryl group, as defined herein, appended to a carboxyl group, as defined herein.
xe2x80x9cArylcarboxylic esterxe2x80x9d and xe2x80x9carylcarboxylxe2x80x9d refer to an aryl group, as defined herein, appended to a carboxylic ester group, as defined herein.
xe2x80x9cCarboxamidoxe2x80x9d refers to xe2x80x94C(O)N(R51)(R57), wherein R51 and R57 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
xe2x80x9cAlkylcarboxamidoxe2x80x9d refers to an alkyl group, as defined herein, appended to a carboxamido group, as defined herein.
xe2x80x9cArylcarboxamidoxe2x80x9d refers to an aryl group, as defined herein, appended to a carboxamido group, as defined herein.
xe2x80x9cUreaxe2x80x9d refers to xe2x80x94N(R59)xe2x80x94C(O)N(R51)(R57) wherein R51, R57, and R59 are each independently a hydrogen atom, an alkyl group, an aryl group or an arylheterocyclic ring, as defined herein, or R51 and R57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
The invention is based on the unexpected discovery that the novel aryl substituted compounds described herein are COX-2 selective inhibitors. These novel compounds can optionally be nitrosated and/or nitrosylated and can be used for the treatment or prevention of inflammation, pain and fever; treatment and/or improvement of the gastrointestinal properties of COX-2 selective inhibitors; facilitation of wound healing; for treatment and/or prevention of renal toxicity and cyclooxygenase-2 mediated disorders; and for the improvement of the cardiovascular profile of COX-2 selective inhibitors.
The COX-2 selective inhibitors, that are optionally nitrosated and/or nitrosylated, can be used alone or in conjunction with one or more compounds that donate, release or transfer nitric oxide and/or stimulate endogenous production of NO and/or EDRF in vivo and/or is a substrate for nitric oxide synthase, and/or with one or more therapeutic agents, such as for example, steroids, nonsterodal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof.
The invention describes novel COX-2 selective inhibitors that are compounds of Formula (I): 
Y1 is:
(a) xe2x80x94(CR1R2)axe2x80x94;
(b) xe2x80x94(CR1R2)bxe2x80x94A1xe2x80x94;
(c) xe2x80x94A1xe2x80x94(CR1R2)bxe2x80x94;
(d) xe2x80x94CR1R2xe2x80x94A1xe2x80x94CR1R2xe2x80x94; or
(e) xe2x80x94CR1xe2x95x90;
Z1 is:
(a) mono-, di- or tri-substituted phenyl or 2-naphthyl, wherein the substituents are each independently:
(1) hydrogen;
(2) halo;
(3) lower alkyl;
(4) haloalkyl;
(5) alkylthio;
(6) xe2x80x94NR4R5;
(7) xe2x80x94C(O)-lower alkyl;
(8) xe2x80x94(CH2)axe2x80x94C(O)Oxe2x80x94R6;
(9) xe2x80x94OR11; or
(10) xe2x80x94(CReRf)qxe2x80x94Uxe2x80x94V
(b) mono-, di- or tri-substituted cycloalkyl or heterocyclic ring, wherein the substituents are each independently:
(1) hydrogen;
(2) halo;
(3) lower alkyl;
(4) haloalkyl;
(5) alkylthio;
(6) xe2x80x94NR4R5;
(7) xe2x80x94C(O)-lower alkyl;
(8) xe2x80x94(CH2)qxe2x80x94C(O)Oxe2x80x94R6;
(9) xe2x80x94OR11;
(10) xe2x80x94(CReRf)qxe2x80x94Uxe2x80x94V;
(11) oxo; or
(12) thial;
(c) alkyl; and the bond between Y1 and Z1 may be a single bond or a double bond such that the valencies are satisfied;
A1 is:
(a) oxygen;
(b) thio;
(c) sulfinyl;
(d) sulfonyl; or
(c) xe2x80x94N(R12)xe2x80x94;
xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 is:
(a) xe2x80x94CR7xe2x95x90CR8xe2x80x94Nxe2x95x90;
(b) xe2x80x94CR7xe2x95x90Nxe2x80x94CR xe2x95x90;
(c) xe2x80x94Nxe2x95x90CR7xe2x80x94CR8xe2x95x90;
(d) xe2x80x94CR8xe2x95x90CR7xe2x80x94Nxe2x95x90;
(e) xe2x80x94CR8xe2x95x90Nxe2x80x94CR7xe2x95x90;
(f) xe2x80x94Nxe2x95x90CR8xe2x80x94CR7xe2x95x90;
(g) xe2x80x94Nxe2x95x90Nxe2x80x94CR7xe2x95x90;
(h) xe2x80x94Nxe2x95x90Nxe2x80x94CR8xe2x95x90;
(i) xe2x80x94CR7xe2x95x90Nxe2x80x94Nxe2x95x90;
(j) xe2x80x94CR8xe2x95x90Nxe2x80x94Nxe2x95x90;
(k) xe2x80x94Nxe2x95x90CR7xe2x80x94Nxe2x95x90;
(l) xe2x80x94Nxe2x95x90CR8xe2x80x94Nxe2x95x90;
(m) xe2x80x94CR7xe2x80x2xe2x95x90CR7xe2x80x94CR8xe2x95x90; or
(n) xe2x80x94CR7xe2x95x90CR8xe2x80x94CR7;
R1 and R2 are each independently:
(a) hydrogen;
(b) lower alkyl;
(c) substituted lower alkyl;
(d) lower alkoxy;
(e) lower haloalkyl; or
(f) halo; or
R1 and R2 taken together are;
(a) oxo; or
(b) thial
R3 is:
(a) xe2x80x94S(O)2xe2x80x94CH3;
(b) xe2x80x94S(O)2xe2x80x94NH2;
(c) xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94C(O)xe2x80x94CF3;
(d) xe2x80x94S(O)(NH)xe2x80x94NH2;
(e) xe2x80x94S(O)(NH)xe2x80x94CH3;
(f) xe2x80x94S(O)(NH)xe2x80x94N(H)xe2x80x94C(O)xe2x80x94CF3;
(g) xe2x80x94S(O)2-haloalkyl; or
(h) xe2x80x94CH2xe2x80x94Uxe2x80x94V
R4 is:
(a) hydrogen;
(b) substituted lower alkyl
(c) cycloalkyl
(d) cycloalkylalkyl;
(e) lower alkenyl;
(f) lower alkoxy;
(g) alkylcarbonyl;
(h) carboxylic ester;
(i) carboxamido;
(j) (arylcarbonyl;
(k) alkylsulfonyl;
(l) arylsufonyl;
(m) alkylarylsulfonyl; or
(n) arylalkylsulfonyl;
R5 is:
(a) hydrogen; or
(b) lower alkyl; or
R4 and R5 taken together with the nitrogen to which they are attached form a heterocyclic ring;
R6 is:
(a) lower alkyl; or
(b) arylalkyl;
R7 is:
(a) hydrogen;
(b) halo;
(c) cyano;
(d) lower alkyl optionally substituted with:
(1) halo;
(2) alkoxy;
(3) aryloxy;
(4) cycloalkoxy;
(5) ester;
(6) carbamoyl;
(7) xe2x80x94NR4R5;
(8) phenyl optionally substituted with:
(i) halo;
(ii) hydroxy;
(iii) lower alkyl; or
(iv) alkoxy;
(9) cyano;
(10) xe2x80x94C(O)xe2x80x94H
(11) alkylcarbonyl;
(12) carboxylic ester;
(13) carboxamido; or
(14) heterocyclic ring;
(e) haloalkyl;
(f) lower alkenyl optionally substituted with:
(1) cyano;
(2) xe2x80x94C(O)xe2x80x94H
(3) alkycarbonyl;
(4) arylcarbonyl;
(5) xe2x80x94C(O)-cycloalkyl;
(6) xe2x80x94C(O)-heterocyclic ring;
(7) carboxylic ester;
(8) nitro; or
(9) xe2x80x94NR4R5;
(g) nitro;
(h) xe2x80x94NR4R5;
(i) xe2x80x94S(O)oR9;
(j) xe2x80x94S(O)oNR5R10;
(k) xe2x80x94C(O)xe2x80x94H;
(l) alkylcarbonyl;
(m) arylcarbonyl;
(n) xe2x80x94C(O)-cycloalkyl;
(o) xe2x80x94C(O)-heterocyclic ring;
(p) carboxylic ester;
(q) carboxamido;
(r) alkoxy;
(s) aryloxy;
(t) cycloalkoxy;
(u) ester;
(v) carbamoyl; or
(w) xe2x80x94D
R7xe2x80x2 is:
(a) hydrogen;
(b) halo; or
(c) xe2x80x94D
R8 is:
(a) hydrogen;
(b) halo;
(c) lower alkyl
(d) lower alkoxy;
(e) lower haloalkyl;
(f) lower alkylthio; or
(g) xe2x80x94D
alternatively, R7 and R8 when substituents on adjacent carbon atoms may be taken together with the carbons to which they are attached to form an aromatic or nonaromatic 5-7 membered carbocyclic or heterocyclic ring system containing from 1-3 heteroatoms selected from nitrogen, oxygen or sulfur. All carbons in the 5-7 membered carbocyclic or heterocyclic ring system are substituted with sufficient R7 or R8 variables to satisfy the tetravalency of the ring carbon atoms.
R9 is:
(a) lower alkyl;
(b) haloalkyl;
(c) phenyl; or
(d) benzyl;
R10 is:
(a) hydrogen;
(b) lower alkyl;
(c) aryl;
(d) cycloalkyl;
(e) cycloalkylalkyl;
(f) lower alkenyl; or
(g) lower alkoxy;
R11 is:
(a) lower alkyl;
(b) lower haloalkyl;
(c) alkoxyalkyl;
(d) alkylcarbonyl;
(e) arylalkylcarbonyl;
(f) carboxamido; or
(g) arylcarbonyl;
R12 is:
(a) lower alkyl;
(b) hydrogen; or
(c) xe2x80x94C(O)H;
R13 is:
(a) hydrogen;
(b) halogen;
(c) lower alkyl;
(d) lower alkoxy; or
(e) lower haloalkyl;
a is an integer equal to 1 or 3;
b is an integer equal to 2 or 3;
o is an integer from 0-2;
D is xe2x80x94Wkxe2x80x94Elxe2x80x94(C(Re)(Rf))pxe2x80x94Ecxe2x80x94(C(Re)(Rf))xxe2x80x94Wdxe2x80x94(C(Re)(Rf))yxe2x80x94Wixe2x80x94Ejxe2x80x94Wgxe2x80x94(C(Re)(Rf))zxe2x80x94Uxe2x80x94V;
Wherein c, d, g, i, j, k and l are each independently an integer from 0 to 3;
p, x, y and z are each independently an integer from 0 to 10;
W at each occurrence is independently:
(a) xe2x80x94C(O)xe2x80x94;
(b) xe2x80x94C(S)xe2x80x94;
(c) xe2x80x94Txe2x80x94;
(d) xe2x80x94(C(Re)(Rf))hxe2x80x94;
(e) alkyl;
(f) aryl;
(g) heterocyclic ring;
(h) arylheterocyclic ring, or
(i) xe2x80x94(CH2CH2O)qxe2x80x94;
E at each occurrence is independently:
(a) xe2x80x94Txe2x80x94;
(b) alkyl;
(c) aryl;
(d) xe2x80x94(C(Re)(Rf))hxe2x80x94;
(e) heterocyclic ring;
(f) arylheterocyclic ring; or
(g) xe2x80x94(CH2CH2O)qxe2x80x94;
h is an integer form 1 to 10;
q is an integer from 1 to 5;
Re and Rf are each independently:
(a) hydrogen;
(b) alkyl;
(c) cycloalkoxy;
(d) halogen;
(e) hydroxy;
(f) hydroxyalkyl;
(g) alkoxyalkyl;
(h) arylheterocyclic ring;
(i) alkylaryl;
(j) cycloalkylalkyl;
(k) heterocyclicalkyl;
(l) alkoxy;
(m) haloalkoxy;
(n) amino;
(o) alkylamino;
(p) dialkylamino;
(q) arylamino;
(r) diarylamino;
(s) alkylarylamino;
(t) alkoxyhaloalkyl;
(u) haloalkoxy;
(v) sulfonic acid;
(w) alkylsulfonic acid;
(x) arylsulfonic acid;
(y) arylalkoxy;
(z) alkylthio;
(aa) arylthio;
(bb) cyano;
(cc) aminoalkyl;
(dd) aminoaryl;
(ee) alkoxy;
(ff) aryl;
(gg) arylalkyl;
(hh) alkylaryl;
(ii) carboxamido;
(jj) alkylcarboxamido;
(kk) arylcarboxamido;
(ll) amidyl;
(mm) carboxyl;
(nn) carbamoyl;
(oo) alkylcarboxylic acid;
(pp) arylcarboxylic acid;
(qq) alkylcarbonyl;
(rr) arylcarbonyl;
(ss) ester;
(tt) carboxylic ester;
(uu) alkylcarboxylic ester;
(vv) arylcarboxylic ester;
(ww) haloalkoxy;
(xx) sulfonamido;
(yy) alkylsulfonamido;
(zz) arylsulfonamido;
(aaa) sulfonic ester;
(bbb) carbamoyl;
(ccc) urea;
(ddd) nitro; or
(eee) xe2x80x94(C(Re)(Rf))kxe2x80x94Uxe2x80x94V; or
Re and Rf taken together with the carbon to which they are attached are:
(a) oxo;
(b) thial;
(c) aryl;
(d) heterocyclic ring;
(e) cycloalkyl group; or
(f) bridged cycloalkyl group;
k is an integer from 1 to 2;
U is:
(a) oxygen;
(b) sulfur; or
(c) xe2x80x94N(Ra)Rixe2x80x94;
V is:
(a) xe2x80x94NO; or
(b) xe2x80x94NO2;
T at each occurrence is independently:
(a) a covalent bond,
(b) carbonyl,
(c) an oxygen,
(d) xe2x80x94S(O)oxe2x80x94; or
(e) xe2x80x94N(Ra)Rixe2x80x94;
Ra is:
(a) a lone pair of electron;
(b) hydrogen; or
(c) lower alkyl;
Ri is:
(a) hydrogen;
(b) alkyl;
(c) aryl;
(d) alkylcarboxylic acid;
(e) aryl carboxylic acid;
(f) alkylcarboxylic ester;
(g) arylcarboxylic ester;
(h) alkylcarboxamido;
(i) arylcarboxamido;
(j) alkylaryl;
(k) alkylsulfinyl;
(l) alkylsulfonyl;
(m) arylsulfinyl;
(n) arylsulfonyl;
(o) sulfonamido;
(p) carboxamido;
(q) carboxylic ester;
(r) aminoalkyl;
(s) aminoaryl;
(t) xe2x80x94CH2xe2x80x94C(Uxe2x80x94V)(Re)(Rf); or
(u) xe2x80x94(N2O2xe2x80x94)xe2x88x92xc2x7M+, wherein M+is an organic or inorganic cation.
In cases where Re and Rf are a heterocyclic ring or Re and Rf taken together with the carbon atoms to which they are attached are a heterocyclic ring, then Ri can be a substituent on any disubstituted nitrogen contained within the radical where Ri is as defined herein.
In cases where multiple designations of variables that are in sequence are selected as a xe2x80x9ccovalent bondxe2x80x9d or the integer selected is 0, the intent is to denote a single covalent bond connecting one radical to another. For example, E0 would denote a covalent bond, while E2 denotes (Exe2x80x94E) and (C(Re)(Rf))2 denotes xe2x80x94C(Re)(Rf)xe2x80x94C(Re)(Rf)xe2x80x94.
Compounds of the invention that have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates. The invention includes within its scope all such isomers and mixtures thereof.
Another aspect of the invention provides processes for making the novel compounds of the invention and to the intermediates useful in such processes. The reactions are performed in solvents appropriate to the reagents and materials used are suitable for the transformations being effected. It is understood by one skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to one skilled in the art. The use of sulfur and oxygen protecting groups is well known for protecting thiol and alcohol groups against undesirable reactions during a synthetic procedure and many such protecting groups are known and described by, for example, Greene and Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley and Sons, New York (1999).
The chemical reactions described herein are generally disclosed in terms of their broadest application for the preparation of the compounds of this invention. The chemical reactions are described by, for example, Smith and March, March""s Advanced Organic Chemistry, Reactions, Mechanisms and Structure, Fifth Edition, John Wiley and Sons, New York (2001) and by Larock, Comprehensive Organic Transformations, VCH Publishers, Inc. (1989). The compounds of the invention can be synthesized in a number of ways well known to one skilled in the art of organic synthesis. The compounds can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or by convention modifications known to one skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily prepared from known starting materials. Methods for the preparation of the compounds, include, but are not limited to, those described below. All references cited herein are hereby incorporated herein by reference in their entirety.
Compounds of Formula (I) wherein X1 is a 4-methylsulfonylphenyl, Y1 is a methylene, hydroxymethylene or carbonyl, Z1 is a substituted phenyl or 2-naphthyl, or heteroaryl and xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 is as defined herein, can be prepared following the general method shown in Scheme 1. 
Coupling of a suitably substituted 4-methylthio-phenylboronic acid with an ortho-bromo, ortho-chloro or ortho-trifluoroacetyl aryl carbaldehyde using methodology introduced by Suzuki (Suzuki et al., J. Am. Chem. Soc., 11:513 (1989), and Kalinin, Russ. Chem. Rev., 60:173 (1991)) gives the phenyl substituted aryl carbaldehyde. Suitable solvents for this coupling include, but are not limited to, toluene, dimethylformamide, dioxane and ethanol. The reaction is carried out in the presence of a palladium catalyst, for example, tetrakis triphenylphosphine palladium or bis(triphenylphosphine)palladium dichloride. Reaction of the carbaldehyde with a substituted aryl lithium or aryl Grignard reagent gives the benzilic alcohol. Oxidation of the methylthio group to the corresponding methylsulfonyl group gives compounds of Formula (I). This oxidation can be accomplished using any reagent known in the art for the oxidation of mercaptans to sulfones. Examples of such reagents include, but are not limited to, OXONE(copyright) in methanol-water (Trost et. al., Tet. Lett., 22:1287, (1981)), hydrogen peroxide, m-chloroperbenzoic acid, or magnesium salt of monoperoxyphthalic acid. Oxidation of the alcohol moiety gives additional compounds of Formula (I). This oxidation can be accomplished using any reagent known in the art for the oxidation of benzilic alcohols to benzilic ketones. Examples of such reagents include, but are not limited to, pyridinium chlorochromate or pyridinium dichromate in methylene chloride and sulfur trioxide-pyridine complex with dimethyl sulfoxide (Parikh-Doering Reagent: J. Am. Chem. Soc., 89:5505 (1967)). Reduction of the alcohol moiety gives additional compounds of Formula (I). This reduction can be accomplished using any reagent known in the art for the reduction of benzilic alcohols. Examples of such reagents include, but are not limited to, hydrogen and a palladium catalyst such as palladium on charcoal, triethylsilane and trifluoroacetic acid or trifluoroacetic acid and sodium borohydride.
Compounds of Formula (I), wherein X1 is a 4-methylsulfonylphenyl, Y1 is a methylidene or a methylene, Z1 is a cycloalkyl or alkyl group and q and xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 are as defined herein, can be prepared following the general method shown in Scheme 2. 
Wittig coupling of the phenyl substituted aryl carbaldehydes with a cycloalkyl phosphorane, an alkyl phosphorane or a phosphonate anion gives the substituted alkenes. Phosphoranes may be prepared from the corresponding phosphonium salts by treatment with a base. Examples of bases used to prepare phosphoranes from phosphonium salts include, but are not limited to, an alkyl lithium, sodium hydride, lithium diisopropyl amide, or sodium alkoxide. Phosphonium salts are prepared from a phosphine and a cycloalkyl or alkyl halide. Phosphonates may be prepared from a phosphite and a cycloalkyl or alkyl halide that may be converted to the phosphonate anion by treatment with a strong base, such as, for example, lithium diisopropyl amide or lithium hexamethyldisilazide. Oxidation of the methylthio group to the corresponding methylsulfonyl group as described herein gives compounds of Formula (I). Reduction of the double bond gives additional compounds of Formula (I). This reduction can be accomplished using any reagent known in the art for the reduction of alkenes. Examples of such reagents include, but are not limited to, hydrogen and a palladium catalyst such as palladium on charcoal.
Compounds of Formula (I) wherein X1 is a 4-methylsulfonylphenyl, Y1 is a methylene, hydroxymethylene or carbonyl, Z1 is a substituted phenyl or 2-naphthyl, or heteroaryl and xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 is selected such that it forms a substituted 2H-benzo(d)1,3-dioxolene ring, can be prepared following the general method shown in Scheme 3. 
Suzuki coupling of 6-bromo-2H-benzo(d)1,3-dioxolene-5-carbaldehyde (Khanapure et. al., J. Org. Chem., 55:1471 (1990)) with 4-methylthiophenylboronic acid using conditions described herein gives the biaryl product. Reaction of the carbaldehyde with a substituted aryl lithium or aryl Grignard reagent gives the benzilic alcohol. Oxidation of the methylthio group to the corresponding methylsulfonyl group using the conditions described herein gives compounds of Formula (I). Oxidation of the alcohol using the conditions described herein gives additional compounds of Formula (I). Reduction of the alcohol using the conditions described herein gives additional compounds of Formula (I).
Compounds of Formula (I), wherein X1 is a 4-methylsulfonylphenyl, Y1 is a methylidene or a methylene, Z1 is a cycloalkyl or alkyl group, q is as defined herein and xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 is selected such that it forms a substituted 2H-benzo(d)1,3-dioxolene ring, can be prepared following the general method shown in Scheme 4. 
Wittig coupling of 6-(4-methylthiophenyl)-2H-benzo(d)1,3-dioxolene-5-carbaldehyde using the reagents and conditions described herein gives the substituted alkenes. Oxidation of the methylthio group to the corresponding methylsulfonyl group as described herein gives compounds of Formula (I). Reduction of the double bond as described herein gives additional compounds of Formula (I).
Compounds of Formula (I) wherein X1 is a 4-methylsulfonylphenyl, Y1 is a methylene, hydroxymethylene or carbonyl, Z1 is a substituted phenyl or 2-naphthyl, or heteroaryl, R is a D group or a precursor to a D group, D is as defined herein and xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 is selected such that it forms a substituted benzoxazole ring, can be prepared following the general method shown in Scheme 5. 
Reduction of the nitro group of 2-chloro-4-hydroxy-5-nitrobenzoic acid (Goldstein et. al. Helv. Chim. Acta., 20:1407 (1937)) gives the amine. This reduction can be accomplished using any reagent known in the art for the reduction of aromatic nitro compounds to amines. Examples of such reagents include, but are not limited to, hydrogenation in the presence of a catalyst such as palladium or platinum on charcoal, zinc, tin or iron and hydrochloric acid in a refluxing aqueous or alcoholic solvent or sodium borohydride in the presence of a catalyst such as nickel or cobalt chloride. Reduction of the carboxylic acid gives the benzilic aldehyde. This reduction can be accomplished using any reagent known in the art for the reduction of carboxylic acids to alcohols with a subsequent oxidation to the carbaldehyde. Examples of such reagents include, but are not limited to, borane in tetrahydrofuran, lithium aluminum hydride in ether or diisobutylaluminum hydride in tetrahydrofuran, hexanes or toluene. Subsequent oxidation to the aldehyde can be accomplished using any reagent known in the art for the oxidation of benzilic alcohols to benzilic aldehydes. Examples of such reagents include, but are not limited to, pyridinium chlorochromate or pyridinium dichromate in methylene chloride orsulfur trioxide-pyridine complex with dimethyl sulfoxide Formation of the substituted benzoxazole ring can be accomplished by treatment of the substituted aniline with a carboxylic acid or carboxylic acid chloride under acidic conditions with the removal of the water formed. Examples of such reagents and conditions used to catalyze the formation of the ring include, but are not limited to, polyphosphoric acid at 100-150xc2x0 C., trimethylsilyl polyphosphate or concentrated sulfuric acid in benzene under reflux with azeotropic removal of the water generated. Suzuki coupling of the chloro substituted benzoxazole with 4-methylthiopheny boronic acid using conditions described herein gives the biaryl product. Reaction of the carbaldehyde with a substituted aryl lithium or aryl Grignard reagent gives the benzilic alcohol. Oxidation of the methylthio group to the corresponding methylsulfonyl group using the conditions described herein gives compounds of Formula (I). Oxidation of the alcohol using the conditions described herein gives additional compounds of Formula (I). Reduction of the alcohol using the conditions described herein gives additional compounds of Formula (I).
Compounds of Formula (I), wherein X1 is a 4-methylsulfonylphenyl, Y1 is a methylidene or a methylene, Z1 is a cycloalkyl or alkyl group, R is a D group or a precursor to a D group, wherein D and q are as defined herein and xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 is selected such that it forms a substituted benzoxazole ring, can be prepared following the general method shown in Scheme 6. 
Wittig coupling of 2-substituted-6-(4-methylthiophenyl)benzoxazole-5-carbaldehyde using the reagents and conditions described herein gives the substituted alkenes. Oxidation of the methylthio group to the corresponding methylsulfonyl group using the conditions described herein gives compounds of Formula (I). Reduction of the double bond using the conditions described herein gives additional compounds of Formula (I).
Compounds of Formula (I) wherein X1 is a 4-methylsulfonylphenyl, Y1 is a methylene, hydroxymethylene, or carbonyl, Z1 is a substituted phenyl or 2-naphthyl, or heteroaryl, R is a D group or a precursor to a D group, wherein D and q are as defined herein and xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 is selected such that it forms a substituted benzthiazole ring, can be prepared following the general method show n in Scheme 7. 
Reduction of the nitro groups of 2,2xe2x80x2-dichloro-5,5xe2x80x2-dinitro-4,4xe2x80x2-disulfanediyl-di-benzoic acid (Goldstein et. al. Helv. Chim. Acta., 21:1513 (1938)) using the reagents and conditions described herein gives the diamine. Reduction of the disulfide gives the thiol. This reduction can be accomplished using any reagent known in the art for the reduction of disulfides to thiols. Examples of such reagents include, but are not limited to, zinc and acetic acid or dilute mineral acid or triphenylphosphine in water. Conversion of the carboxylic acid to the carboxylic acid chloride can be accomplished using any reagent known in the art for the conversion of carboxylic acids to carboxylic acid chlorides. Examples of such reagents include, but are not limited to, thionyl chloride or oxalyl chloride with or without a catalytic amount of dimethylforamide, phosphorus pentachloride or triphenylphosphine and carbon tetrachloride. Reduction of the carboxylic acid chloride gives the aldehyde. This reduction can be accomplished using any reagent known in the art for the conversion of carboxylic acid chlorides directly to aldehydes. Examples of such reagents include, but are not limited to, catalytic hydrogenation with palladium on barium sulfate (Rosenmund reduction), sodium borohydride and cadmium chloride or lithium tri-tert-butoxyaluminum hydride in diglyme at xe2x88x9278xc2x0 C. Formation of the substituted benzthiazole ring can be accomplished by treatment of the substituted aniline with a carboxylic acid or carboxylic acid chloride under acidic conditions with removal of the water formed. Examples of such reagents and conditions used to catalyze the formation of the ring include, but are not limited to, polyphosphoric acid at 100-150xc2x0 C., trimethylsilyl polyphosphate or concentrated sulfuric acid in benzene under reflux with azeotropic removal of the water generated. Suzuki coupling of the chloro-substituted benzthiazole with 4-methylthiophenylboronic acid using conditions described herein gives the biaryl product. Reaction of the carbaldehyde with a substituted aryl lithium or aryl Grignard reagent gives the benzilic alcohol. Oxidation of the methylthio group to the corresponding methylsulfonyl group using the conditions described herein gives compounds of Formula (I). Oxidation of the alcohol using the conditions described herein gives additional compounds of Formula (I). Reduction of the alcohol using the conditions described herein gives additional compounds of Formula (I).
Compounds of Formula (I), wherein X1 is a 4-methylsulfonylphenyl, Y1 is a methylidene or a methylene, Z1 is a cycloalkyl or alkyl group, R is a D group or a precursor to a D group, wherein D and q are as defined herein and xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 is selected such that it forms a substituted benzthiazole ring, can be prepared following the general method shown in Scheme 8. 
Wittig coupling of 2-substituted-6-(4-methylthiophenyl)benzthiazole-5-carbaldehyde using the conditions described herein gives the substituted alkenes. Oxidation of the methylthio group to the corresponding methylsulfonyl group using the conditions described herein givess compounds of Formula (I). Reduction of the double bond using the conditions described herein gives additional compounds of Formula (I).
Compounds of Formula (I) wherein X1 is a 4-methylsulfonylphenyl, Y1 is a methylene, hydroxymethylene or carbonyl, Z1 is a substituted phenyl, 2-naphthyl, or heteroaryl, R is a D group or a precursor to a D group, D is as defined herein and xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 is selected such that it forms a substituted benzoxazole ring, can be prepared following the general method shown in Scheme 9. 
Protection of the of the amine group of 4-amino-2-chloro-5-nitro-benzoic acid (Goldstein et. al., Helv. Chim, Acta., 20:1407 (1937)) as the N-carbobenzyloxy derivative can be accomplished by reacting the amine with benzyl chloroformate. Reduction of the nitro group of 2-chloro-5-nitro-4-((phenylmethoxy)carbonylamino)benzoic acid using the reagents and conditions described herein gives the amine. Treatment of the amine with nitrous acid followed by conversion of the diazonium group to a hydroxy group gives the phenol. Conversion of the aromatic primary amine to the diazonium salt can be accomplished using any reagent known in the art for the conversion of anilines to diazonium salts, such as, for example, sodium nitrite and sulfuric acid to form the diazonium salt. Treatment of the diazonium salt with aqueous boiling dilute sulfuric acid gives the phenol. Alternatively, treatment of an aqueous solution of the diazonium salt containing an excess of cupric nitrate with cuprous oxide gives the phenol. Deprotection of carbamate protecting group by hydrogenation in the presence of a catalyst, such as, for example, palladium on carbon gives the amine. Reduction of the carboxylic acid or acid chloride to the benzilic alcohol and the oxidizing the benzilic alcohol to the aldehyde or, alternatively, reducing the carboxylic acid via the carboxylic acid chloride directly to the carbaldehyde using the conditions described herein gives the aldehyde. Formation of the benzoxazole ring using the conditions described herein, followed by Suzuki coupling of the chloro substituted benzoxazole with 4-methylthiophenylboronic acid using the conditions described herein gives the biaryl product. Reaction of the carbaldehyde with a substituted aryl lithium or aryl Grignard reagent gives the benzilic alcohol. Oxidation of the methylthio group to the corresponding methylsulfonyl group using the conditions described herein gives compounds of Formula (I). Oxidation of the alcohol using the conditions described herein gives additional compounds of Formula (I). Reduction of the alcohol using the conditions described herein gives additional compounds of Formula (I).
Compounds of Formula (I), wherein X1 is a 4-methylsulfonylphenyl, Y1 is a methylidene or a methylene, Z1 is a cycloalkyl or alkyl group, R is a D group or a precursor to a D group, wherein D and q are as defined herein and xe2x80x94Jxe2x95x90Kxe2x80x94Lxe2x95x90 is selected such that it forms a substituted benzoxazole ring, can be prepared following the general method shown in Scheme 10. 
Wittig coupling of the 2-substituted 5-(4-methylthiophenyl)benzoxazole-6-carbaldehyde using the conditions described herein gives the substituted alkenes. Oxidation of the methylthio group to the corresponding methylsulfonyl group using the conditions described herein gives compounds of Formula (I). Reduction of the double bond using the conditions described herein gives additional compounds of Formula (I).
The compounds of Formula (I) can be nitro sated and/or nitrosylated through one or more sites such as oxygen, sulfur and/or nitrogen using the methods described in the examples herein and using conventional methods known to one skilled in the art. For example, known methods for nitrosating and nitrosylating compounds are described in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae et al, Org. Prep. Proc. Int., 15(3):165-198 (1983), the disclosures of each of which are incorporated by reference herein in their entirety. The methods of nitrosating and/or nitrosylating the compounds described in the examples herein and in these references can be applied by one skilled in the art to produce any of the nitro sated and/or nitrosylated compounds of Formula (I) described herein. The nitrosated and/or nitrosylated compounds of Formula (I) (i.e. nitrosated and/or nitrosylated COX-2 selective inhibitors) of the invention donate, transfer or release a biologically active form of nitrogen monoxide (nitric oxide).
Nitrogen monoxide can exist in three forms: NOxe2x88x92 (nitroxyl), NOxc2x7 (uncharged nitric oxide) and NO+ (nitrosonium). NOxc2x7 is a highly reactive short-lived species that is potentially toxic to cells. This is critical because the pharmacological efficacy of NO depends upon the form in which it is delivered. In contrast to the nitric oxide radical (NOxc2x7), nitrosonium (NO+) does not react with O2 or O2 species, and functionalities capable of transferring and/or releasing NO+ and NOxe2x88x92 are also resistant to decomposition in the presence of many redox metals. Consequently, administration of charged NO equivalents (positive and/or negative) is a more effective means of delivering a biologically active NO to the desired site of action.
Compounds contemplated for use in the invention (e.g., COX-2 selective inhibitors that can be optionally nitrosated and/or nitrosylated) are, optionally, used in combination with nitric oxide and compounds that release nitric oxide or otherwise directly or indirectly deliver or transfer a biologically active form of nitrogen monoxide to a site of its intended activity, such as on a cell membrane in vivo.
The term xe2x80x9cnitric oxidexe2x80x9d encompasses uncharged nitric oxide (NOxc2x7) and charged nitrogen monoxide species, preferably charged nitrogen monoxide species, such as nitrosonium ion (NO+) and nitroxyl ion (NOxe2x88x92). The reactive form of nitric oxide can be provided by gaseous nitric oxide. The nitrogen monoxide releasing, delivering or transferring compounds have the structure Fxe2x80x94NO, wherein F is a nitrogen monoxide releasing, delivering or transferring moiety, and include any and all such compounds which provide nitrogen monoxide to its intended site of action in a form active for its intended purpose. The term xe2x80x9cNO adductsxe2x80x9d encompasses any nitrogen monoxide releasing, delivering or transferring compounds, including, for example, S-nitrosothiols, nitrites, nitrates, S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines, (NONOates), (E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexeneamide (FK-409), (E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexeneamines, N-((2Z, 3E)-4-ethyl-2-(hydroxyimino)-6-methyl-5-nitro-3-heptenyl)-3-pyridinecarboxamide (FR 146801), nitrosoamines, furoxans as well as substrates for the endogenous enzymes which synthesize nitric oxide. NONOates include, but are not limited to, (Z)-1-(N-methyl-N-(6-(N-methyl-ammoniohexyl)amino))diazen-1-ium-1,2-diolate (xe2x80x9cMAHMA/NOxe2x80x9d), (Z)-1-(N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium-1,2-diolate diolate (xe2x80x9cPAPA/NOxe2x80x9d), (Z)-1-(N-(3-aminopropyl)-N-(4-(3-aminopropylammonio)butyl)-amino)diazen-1-ium-1,2-diolate (spermine NONOate or xe2x80x9cSPER/NOxe2x80x9d) and sodium (Z)-1-(N,N-diethylamino)diazenium-1,2-diolate (diethylamine NONOate or xe2x80x9cDEA/NOxe2x80x9d) and derivatives thereof. NONOates are also described in U.S. Pat. Nos. 6,232,336, 5,910,316 and 5,650,447, the disclosures of which are incorporated herein by reference in their entirety. The xe2x80x9cNO adductsxe2x80x9d can be mono-nitrosylated, poly-nitrosylated, mono-nitrosated and/or poly-nitrosated at a variety of naturally susceptible or artificially provided binding sites for biologically active forms of nitrogen monoxide.
One group of NO adducts is the S-nitrosothiols, which are compounds that include at least one xe2x80x94Sxe2x80x94NO group. These compounds include S-nitroso-polypeptides (the term xe2x80x9cpolypeptidexe2x80x9d includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated sugars; S-nitrosylated, modified and unmodified, oligonucleotides (preferably of at least 5, and more preferably 5-200 nucleotides); straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds. S-nitrosothiols and methods for preparing them are described in U.S. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae et al, Org. Prep. Proc. Int., 15(3): 165-198 (1983), the disclosures of each of which are incorporated by reference herein in their entirety.
Another embodiment of the invention is S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof. Such compounds include, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, S-nitroso-cysteinyl-glycine, and the like.
Suitable S-nitrosylated proteins include thiol-containing proteins (where the NO group is attached to one or more sulfur groups on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator (TPA) and cathepsin B; transport proteins, such as lipoproteins; heme proteins, such as hemoglobin and serum albumin; and biologically protective proteins, such as immunoglobulins, antibodies and cytokines. Such nitrosylated proteins are described in WO 93/09806, the disclosure of which is incorporated by reference herein in its entirety. Examples include polynitrosylated albumin where one or more thiol or other nucleophilic centers in the protein are modified.
Other examples of suitable S-nitrosothiols include:
(i) HS(C(Re)(Rf))mSNO;
(ii) ONS(C(Re)(Rf))mRe; and
(iii) H2Nxe2x80x94CH(CO2H)xe2x80x94(CH2)mxe2x80x94C(O)NHxe2x80x94CH(CH2SNO)xe2x80x94C(O)NHxe2x80x94CH2xe2x80x94CO2H;
wherein m is an integer from 2 to 20; Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a carbamoyl, a urea, a nitro, xe2x80x94Txe2x80x94Qxe2x80x94, or (C(Re)(Rf))kxe2x80x94Txe2x80x94Q, or Re and Rf taken together are an oxo, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Q is xe2x80x94NO or xe2x80x94NO2; and T is independently a covalent bond, a carbonyl, an oxygen, xe2x80x94S(O)oxe2x80x94 or xe2x80x94N(Ra)Rixe2x80x94, wherein o is an integer from 0 to 2, Ra is a lone pair of electrons, a hydrogen or an alkyl group; Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, xe2x80x94CH2xe2x80x94C(Txe2x80x94Q)(Re)(Rf), or xe2x80x94(N2O2xe2x80x94)xe2x88x92xc2x7M+, wherein M+ is an organic or inorganic cation; with the proviso that when Ri is xe2x80x94CH2xe2x80x94C(Txe2x80x94Q)(Re)(Rf) or xe2x80x94(N2O2xe2x80x94)xc2x7M+; then xe2x80x9cxe2x80x94Txe2x80x94Qxe2x80x9d can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
In cases where Re and Rf are a heterocyclic ring or taken together Re and Rf are a heterocyclic ring, then Ri can be a substituent on any disubstituted nitrogen contained within the radical wherein Ri is as defined herein.
Nitrosothiols can be prepared by various methods of synthesis. In general, the thiol precursor is prepared first, then converted to the S-nitrosothiol derivative by nitrosation of the thiol group with NaNO2 under acidic conditions (pH is about 2.5) which yields the S-nitroso derivative. Acids which can be used for this purpose include aqueous sulfuric, acetic and hydrochloric acids. The thiol precursor can also be nitrosylated by reaction with an organic nitrite such as tert-butyl nitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate in an inert solvent.
Another group of NO adducts for use in the invention, where the NO adduct is a compound that donates, transfers or releases nitric oxide, include compounds comprising at least one ONxe2x80x94Oxe2x80x94, ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-group. The compounds that include at least one ONxe2x80x94Oxe2x80x94, ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-group are preferably ONxe2x80x94Oxe2x80x94, ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-polypeptides (the term xe2x80x9cpolypeptidexe2x80x9d includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); ONxe2x80x94Oxe2x80x94, ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); ONxe2x80x94Oxe2x80x94, ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-sugars; ONxe2x80x94Oxe2x80x94, ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-modified or unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); ONxe2x80x94Oxe2x80x94, ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbons; and ONxe2x80x94Oxe2x80x94, ONxe2x80x94Nxe2x80x94 or ONxe2x80x94C-heterocyclic compounds.
Another group of NO adducts for use in the invention include nitrates that donate, transfer or release nitric oxide, such as compounds comprising at least one O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-group. Preferred among these compounds are O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-polypeptides (the term xe2x80x9cpolypeptidexe2x80x9d includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-sugars; O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-modified and unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbons; and O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-heterocyclic compounds. Preferred examples of compounds comprising at least one O2Nxe2x80x94Oxe2x80x94, O2Nxe2x80x94Nxe2x80x94, O2Nxe2x80x94Sxe2x80x94 or O2Nxe2x80x94C-group include isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityl tetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol, propatylnitrate and organic nitrates with a sulfhydryl-containing amino acid such as, for example SPM 3672, SPM 5185, SPM 5186 and those disclosed in U.S. Pat. Nos. 5,284,872, 5,428,061, 5,661,129, 5,807,847 and 5,883,122 and in U.S. Provisional Application No. 60/311,175 and in WO 97/46521 and WO 00/54756, the disclosures of each of which are incorporated by reference herein in their entirety.
Another group of such adducts are N-oxo-N-nitrosoamines that donate, transfer or release nitric oxide and are represented by the formula: R1R2Nxe2x80x94N(Oxe2x80x94M+)xe2x80x94NO, where R1 and R2 are each independently a polypeptide, an amino acid, a sugar, a modified or unmodified oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and where M+ is an organic or inorganic cation, such as, for example, an alkyl substituted ammonium cation or a Group I metal cation.
The invention is also directed to compounds that stimulate endogenous NO or elevate levels of endogenous endothelium-derived relaxing factor (EDRF) in vivo or are substrates for nitric oxide synthase. Such compounds include, for example, L-arginine, L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated and nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylated L-homoarginine), precursors of L-arginine and/or physiologically acceptable salts thereof, including, for example, citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids, inhibitors of the enzyme arginase (e.g., N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid) and the substrates for nitric oxide synthase, cytokines, adenosin, bradykinin, calreticulin, bisacodyl, and phenolphthalein. EDRF is a vascular relaxing factor secreted by the endothelium, and has been identified as nitric oxide (NO) or a closely related derivative thereof (Palmer et al, Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).
The invention is also based on the discovery that compounds and compositions of the invention may be used in conjunction with other therapeutic agents for co-therapies, partially or completely, in place of other conventional antiinflammatory compounds, such as, for example, together with steroids, NSAIDs, 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, HMG-CoA inhibitors, H2 receptor antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opiods, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof.
Leukotriene A4 (LTA4) hydrolase inhibitors refer to compounds that selectively inhibit leukotriene A4 hydrolase with an IC50 of less than about 10 xcexcM, and preferably with an IC50 of less than about 1 xcexcM. Suitable LTA4 hydrolase inhibitors include, but are not limited to, RP-64966, (S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acid benzyl ester, N-(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine, 7-(4-(4-ureidobenzyl)phenyl) heptanoic acid and 3 (3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithium salt, and mixtures thereof.
Suitable LTB4 receptor antagonists include, but are not limited to, ebselen, linazolast, ontazolast; WAY 121006; Bay-x-1005; BI-RM-270; CGS-25019C; ETH-615; MAFP; TMK-688; T-0757; LY 213024, LY 210073, LY 223982, LY 233469, LY 255283, LY 264086, LY 292728 and LY 293111; ONO-LB457, ONO-4057, and ONO-LB-448, S-2474, calcitrol; PF 10042; Pfizer 105696; RP 66153; SC-53228, SC-41930, SC-50605, SC-51146 and SC-53228;
SB-201146 and SBD-209247; SKF-104493; SM 15178; TMK-688; BPC 15, and mixtures thereof. The preferred LTB4 receptor antagonists are calcitrol, ebselen, Bay-x-1005, CGS-25019C, ETH-615, LY-293111, ONO-4057 and TMK-688, and mixtures thereof.
Suitable 5-LO inhibitors include, but are not limited to, A-76745, 78773 and ABT761; Bay-x-1005; CMI-392; E-3040; EF-40; F-1322; ML-3000; PF-5901; R-840; rilopirox, flobufen linasolast, lonapolene, masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast, and mixtures thereof. Suitable 5-LO inhibitors are also described more fully in WO 97/29776, the disclosure of which is incorporated herein by reference in its entirety.
Suitable 5-HT agonists, include, but are not limited to, rizatriptan, sumatriptan, naratriptan, zolmitroptan, eleptriptan, almotriptan, ergot alkaloids. ALX 1323, Merck L 741604 SB 220453 and LAS 31416. Suitable 5-HT agonists are described more fully in WO 0025779, and in WO 00/48583. 5-HT agonists refers to a compound that is an agonist to any 5-HT receptor, including but not limited to, 5-HT1 agonists, 5-HT1B agonists and 5-HT1D agonists, and the like.
Suitable steroids, include, but are not limited to, budesonide, dexamethasone, corticosterone, prednisolone, and the like. Suitable steroids are described more fully in the literature, such as in the Merck Index on CD-ROM, Twelfth Edition, Version 12:1, 1996.
Suitable HMG CoA inhibitors, include, but are not limited to, reductase and synthase inhibitors, such as, for example, squalene synthetase inhibitors, benzodiazepine squalene synthase inhibitors, squalene epoxidase inhibitors, acyl-coenzyme A, bile acid sequestrants, cholesterol absorption inhibitors, and the like. Suitable HMG CoA inhibitors include simvastatin, pravastatin, lovastatin, and the like, and are described more fully in U.S. Pat. No. 6,245,797 and WO 99/20110, the disclosures of which are incorporated herein by reference in their entirety.
Suitable NSAIDs, include, but are not limited to, acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, naproxen and the like. Suitable NSAIDs are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617-657; the Merck Index on CD-ROM, Twelfth Edition, Version 12:1, 1996; and in U.S. Pat. Nos. 6,057,347 and 6,297,260 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety.
Suitable H2 receptor anatgonists, include, but are not limited to, cimetidine, roxatidine, rantidine and the like. Suitable H2 receptor antagonists are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901-915; the Merck Index on CD-ROM, Twelfth Edition, Version 12:1, 1996; and in WO 00/28988 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety.
Suitable antineoplastic agents, include but are not limited to, 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, altretamine, anaxirone, aclarubicin and the like. Suitable antineoplastic agents are also described in U.S. Pat. No. 6,025,353 and WO 00/38730, the disclosures of which are incorporated herein by reference in their entirety.
Suitable antiplatelet agents, include but are not limited to, aspirin, ticlopidine, dipyridamole, clopidogrel, glycoprotein IIb/IIIa receptor antagonists, and the like. Suitable antineoplastic agents are also described in WO 99/45913, the disclosure of which is incorporated herein by reference in its entirety.
Suitable antiplatelet agents, include but are not limited to, aspirin, ticlopidine, dipyridamole, clopidogrel, glycoprotein IIb/IIIa receptor antagonists, and the like. Suitable antiplatelet agents are also described in WO 99/45913, the disclosure of which is incorporated herein by reference in its entirety.
Suitable thrombin inhibitors, include but are not limited to, Nxe2x80x2-((1-(aminoiminomethyl)-4-piperidinyl)methyl)-N-(3,3-diphenylpropinyl)-L-proline amide),3-(2-phenylethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylene-carboxamidomethylpyridinyl)-2-pyrazinone, 3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone, and the like. Suitable thrombin inhibitors are also described in WO 00/18352, the disclosure of which is incorporated herein by reference in its entirety.
Suitable thromboxane inhibitors, include but are not limited to thromboxane synthase inhibitors, thromboxane receptor antagonists, and the like. Suitable thromboxane inhibitors, are also described in WO 01/87343, the disclosure of which is incorporated herein by reference in its entirety.
Suitable decongestants include, but are not limited to, phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, levo-desoxyephedrine, and the like.
Suitable antitussives include, but are not limited to, codeine, hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like.
Suitable proton pump inhibitors, include, but are not limited to, omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, and the like. Suitable proton pump inhibitors are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901-915; the Merck Index on CD-ROM, Twelfth Edition, Version 12:1, 1996; and in WO 00/50037 assigned to NitroMed Inc., the disclosures of which are incorporated herein by reference in their entirety.
The compounds and compositions of the invention, may also be used in combination therapies with opioids and other analgesics, including, but not limited to, narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. non-addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, neurokinin 1 receptor antagonists, Substance P antagonists, neurokinin-1 receptor antagonists, sodium channel blockers, N-methyl-D-aspartate receptor antagonists, and mixtures thereof. Preferred combination therapies would be with morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone, Tramadol ((+) enantiomer), DuP 747, Dynorphine A, Enadoline, RP-60180, HN-11608, E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene, nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631, Tramadol ((xe2x88x92) enantiomer), GP-531, acadesine, AKI-1, AKI-2, GP-1683, GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742, SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, CP-99,994, and mixtures thereof.
The compounds and compositions of the invention can also be used in combination with inducible nitric oxide synthase (iNOS) inhibitors. Suitable iNOS inhibitors are disclosed in U.S. Pat. Nos. 5,132,453 and 5,273,875, and in WO 97/38977 and WO 99/18960, the disclosures of each of which are incorporated by reference herein in their entirety.
The invention is also based on the discovery that the administration of a therapeutically effective amount of the compounds and compositions described herein is effective for treating inflammation, pain (both chronic and acute), and fever, such as, for example, analgesic in the treatment of pain, including, but not limited to headaches, migraines, postoperative pain, dental pain, muscular pain, and pain resulting from cancer; as an antipyretic for the treatment of fever, including but not limited to, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains, strains, myositis, neuralgia, synovitis; arthritis, including but not limited to rheumatoid arthritis, degenerative joint disease (osteoarthritis), spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis. For example, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor of the invention. In another embodiment, the patient can be administered a therapeutically effective amount of at least one nitrosated and/or nitrosylated COX-2 selective inhibitor. In another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase. In yet another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and, at least one therapeutic agent, including but not limited to, steroids, nonsterodal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase. The compounds can be administered separately or in the form of a composition.
Another embodiment of the invention provides methods for decreasing and/or preventing gastrointestinal disorders and improving the gastrointestinal properties of the COX-2 selective inhibitor by administering to the patient in need thereof a therapeutically effective amount of the compounds and/or compositions described herein. Such gastrointestinal disorders refer to any disease or disorder of the upper gastrointestinal tract (e.g., esophagus, the stomach, the duodenum, jejunum) including, for example, inflammatory bowel disease, Crohn""s disease, gastritis, irritable bowel syndrome, ulcerative colitis, peptic ulcers, stress ulcers, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, bacterial infections (including, for example, a Helicobacter Pylori associated disease), short-bowel (anastomosis) syndrome, hypersecretory states associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia, and bleeding peptic ulcers that result, for example, from neurosurgery, head injury, severe body trauma or burns. For example, the patient can be administered a therapeutically effective amount of at least one nitrosated and/or nitrosylated COX-2 selective inhibitor of the invention. In another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase. In yet another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one therapeutic agent, including but not limited to, steroids, nonsterodal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase. The compounds can be administered separately or in the form of a composition.
Yet another embodiment of the invention provides methods for facilitating wound healing (such as, for example, ulcer healing) by administering to the patient in need thereof a therapeutically effective amount of the compounds and/or compositions described herein. Wound refers to, and includes, any lesion that is characterized by loss of tissue, and, includes, but are not limited to, ulcers, cuts, bums, and the like. Ulcers refers to lesions of the upper gastrointestinal tract lining that are characterized by loss of tissue, and, include, but are not limited to, gastric ulcers, duodenal ulcers, gastritis, and the like. For example, the patient can be administered a therapeutically effective amount of at least one nitrosated and/or nitrosylated COX-2 selective inhibitor of the invention. In another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one nitric oxide donor. In yet another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one therapeutic agent, and, optionally, at least one nitric oxide donor. The compounds can be administered separately or in the form of a composition.
Another embodiment of the invention provides methods to decrease or reverse renal and other toxicities (such as, for example, kidney toxicity) by administering to a patient in need thereof a therapeutically effective amount of the compounds and/or compositions described herein. For example, the patient can be administered a therapeutically effective amount of at least one nitrosated and/or nitrosylated COX-2 selective inhibitor of the invention. In another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one nitric oxide donor. In yet another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one therapeutic agent, and, optionally, at least one nitric oxide donor. The compounds can be administered separately or in the form of a composition.
Another embodiment of the invention provides methods to treat or prevent disorders resulting from elevated levels of COX-2 by administering to a patient in need thereof a therapeutically effective amount of the compounds and/or compositions described herein. For example, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, of the invention. In another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase. In yet another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one therapeutic agent, including but not limited to, steroids, a nonsterodal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase. The compounds can be administered separately or in the form of a composition.
Disorders resulting from elevated levels of COX-2 (e.g., COX-2 mediated disorders) include, but are not limited to, for example, angiogenisis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis; skin-related conditions, such as, for example, psoriasis, eczema, surface wounds, burns and dermatitis; post-operative inflammation including from ophthalmic surgery, such as, for example, cataract surgery and refractive surgery, and the like; treatment of neoplasia, such as, for example, brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma), such as, for example, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, such as, for example, lip cancer, mouth cancer, esophageal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamus cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body, benign and cancerous tumors, growths, polyps, adenomatous polyps, including, but not limited to, familial adenomatous polyposis, fibrusis resulting from radiation therapy, and the like; treatment of inflammatory processes in diseases, such as, for example, vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin""s disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet""s syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like; treatment of ophthalmic diseases and disorders, such as, for example, retinitis, retinopathies, uveitis, ocular photophobia, acute injury to the eye tissue, glaucoma, inflammation of the eye and elevation of intraocular pressure and the like; treatment of pulmonary inflammation, such as, for example, those associated with viral infections and cystic fibrosis, and the like; treatment of central nervous system disorders, such as, for example, cortical dementias including Alzheimer""s disease, vascular dementia, multi-infarct dementia, pre-senile dementia, alcoholic dementia, senile dementia, and central nervous system damage resulting from stroke, ischemia and trauma, and the like; treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis; treatment of inflammations and/or microbial infections including, for example, inflammations and/or infections of the eyes, ears, nose, throat, and/or skin; treatment and/or prevention of cardiovascular disorders, such as, for example, coronary artery disease, aneurysm, arteriosclerosis, atherosclerosis, including, but not limited to, cardiac transplant atherosclerosis, myocardial infaraction, hypertension, ischemia, embolism, stroke, thrombosis, venous thrombosis, thromboembolism, thrombotic occlusion and reclusion, restenosis, angina, unstable angina, shock, heart failure, coronary plaque inflammation, bacterial-induced inflammation, such as, for example, Chlamydia-induced inflammation, viral induced inflammation, inflammation associated with surgical procedures, such as, for example, vascular grafting, coronary artery bypass surgery, revascularization procedures, such as, for example, angioplasty, stent placement, endarterectomy, vascular procedures involving arteries, veins, capillaries, and the like; treatment and/or prevention of urinary and/or urological disorders, such as, for example, incontinence and the like; treatment and/or prevention of endothelial dysfunctions, such as, for example, diseases accompanying these dysfunctions, endothelial damage from hypercholesterolemia, endothelial damage from hypoxia, endothelial damage from mechanical and chemical noxae, especially during and after drug, and mechanical reopening of stenosed vessels, for example, following percutaneous transluminal angiography (PTA) and percuntaneous transluminal coronary angiography (PTCA), endothelial damage in postinfarction phase, endothelium-mediated reocculusion following bypass surgery, blood supply distrubances in peripheral arteries, as well as, cardiovascular diseases, and the like; disorders treated by the preservation of organs and tissues, such as, for example, for organ transplants, and the like; disorders treated by the inhibition and/or prevention of activation, adhesion and infiltration of neutrophils at the site of inflammation; and disorders treated by the inhibition and/or prevention of platelet aggregation. The compounds and compositions of the invention can also be used as a pre-anesthetic medication in emergency operations to reduce the danger of aspiration of acidic gastric contents.
Another embodiment of the invention provides methods for improving the cardiovascular profile of COX-2 selective inhibitors by administering to a patient in need thereof a therapeutically effective amount of the compounds and/or compositions described herein. For example, the patient can be administered a therapeutically effective amount of at least one nitrosated and/or nitrosylated COX-2 selective inhibitor of the invention. In another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, and at least one nitric oxide donor. In yet another embodiment, the patient can be administered a therapeutically effective amount of at least one COX-2 selective inhibitor, that is optionally nitrosated and/or nitrosylated, at least one of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, and, optionally, at least one nitric oxide donor. The compounds can be administered separately or in the form of a composition.
When administered in vivo, the compounds and compositions of the invention can be administered in combination with pharmaceutically acceptable carriers and in dosages described herein. When the compounds and compositions of the invention are administered as a mixture of at least one COX-2 selective inhibitor and/or at least one nitrosated and/or nitrosylated COX-2 selective inhibitor and/or at least one nitric oxide donor and/or therapeutic agent, they can also be used in combination with one or more additional compounds which are known to be effective against the specific disease state targeted for treatment. The nitric oxide donors, therapeutic agents and/or other additional compounds can be administered simultaneously with, subsequently to, or prior to administration of the COX-2 selective inhibitor and/or nitrosated and/or nitrosylated COX-2 selective inhibitor.
The compounds and compositions of the invention can be administered by any available and effective delivery system including, but not limited to, orally, bucally, parenterally, by inhalation spray, by topical application, by injection, transdermally, or rectally (e.g., by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles, as desired. Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
Transdermal compound administration, which is known to one skilled in the art, involves the delivery of pharmaceutical compounds via percutaneous passage of the compound into the systemic circulation of the patient. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. Other components can be incorporated into the transdermal patches as well. For example, compositions and/or transdermal patches can be formulated with one or more preservatives or bacteriostatic agents including, but not limited to, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and the like. Dosage forms for topical administration of the compounds and compositions can include creams, sprays, lotions, gels, ointments, eye drops, nose drops, ear drops, and the like. In such dosage forms, the compositions of the invention can be mixed to form white, smooth, homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1% or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution. In addition, the compositions can contain polyethylene glycol 400. They can be mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt) as preservative, white petrolatum, emulsifying wax, and tenox II (butylated, hydroxyanisole, propyl gallate, citric acid, propylene glycol). Woven pads or rolls of bandaging material, e.g., gauze, can be impregnated with the compositions in solution, lotion, cream, ointment or other such form can also be used for topical application. The compositions can also be applied topically using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
Solid dosage forms for oral administration can include capsules, tablets, effervescent tablets, chewable tablets, pills, powders, sachets, granules and gels. In such solid dosage forms, the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, effervescent tablets, and pills, the dosage forms can also comprise buffering agents. Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the invention and vegetable oil. Hard gelatin capsules can contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin. Tablets and pills can be prepared with enteric coatings.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Suppositories for vaginal or rectal administration of the compounds and compositions of the invention, such as for treating pediatric fever and the like, can be prepared by mixing the compounds or compositions with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at rectal temperature, such that they will melt in the rectum and release the drug.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer""s solution, and isotonic sodium chloride solution. Sterile fixed oils are also conventionally used as a solvent or suspending medium.
The compositions of this invention can further include conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds. Suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like. The pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds. For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Aqueous suspensions may contain substances which increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol and/or dextran. Optionally, the suspension may also contain stabilizers.
The composition, if desired, can also contain minor amounts of wetting agents, emulsifying agents and/or pH buffering agents. The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like.
Various delivery systems are known and can be used to administer the compounds or compositions of the invention, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules and the like. The required dosage can be administered as a single unit or in a sustained release form.
The bioavailabilty of the compositions can be enhanced by micronization of the formulations using conventional techniques such as grinding, milling, spray drying and the like in the presence of suitable excipients or agents such as phospholipids or surfactants.
The preferred methods of administration of the COX-2 selective inhibitors and compositions for the treatment of gastrointestinal disorders are orally, bucally or by inhalation. The preferred methods of administration for the treatment of inflammation and microbial infections are orally, bucally, topically, transdermally or by inhalation.
The compounds and compositions of the invention can be formulated as pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include, for example, alkali metal salts and addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceuticallly-acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriate organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesuifonic, sulfanilic, stearic, algenic, xcex2-hydroxybutyric, cyclohexylaminosulfonic, galactaric and galacturonic acid and the like. Suitable pharmaceutically-acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from primary, secondary and tertiary amines, cyclic amines, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine and the like. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
While individual needs may vary, determination of optimal ranges for effective amounts of the compounds and/or compositions is within the skill of the art. Generally, the dosage required to provide an effective amount of the compounds and compositions, which can be adjusted by one of ordinary skill in the art, will vary depending on the age, health, physical condition, sex, diet, weight, extent of the dysfunction of the recipient, frequency of treatment and the nature and scope of the dysfunction or disease, medical condition of the patient, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound used, whether a drug delivery system is used, and whether the compound is administered as part of a drug combination.
The amount of a given COX-2 selective inhibitor of the invention that will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques, including reference to Goodman and Gilman, supra; The Physician""s Desk Reference, Medical Economics Company, Inc., Oradell, N.J., 1995; and Drug Facts and Comparisons, Inc., St. Louis, Mo., 1993. The precise dose to be used in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided by the physician and the patient""s circumstances.
The amount of nitric oxide donor in a pharmaceutical composition can be in amounts of about 0.1 to about 10 times the molar equivalent of the COX-2 selective inhibitor. The usual daily doses of the COX-2 selective inhibitors are about 0.001 mg to about 140 mg/kg of body weight per day, preferably 0.005 mg to 30 mg/kg per day, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammations may be effectively treated by the administration of from about 0.01 mg to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day. The compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, and most preferably once per day. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems and are in the same ranges or less than as described for the commercially available compounds in the Physician""s Desk Reference, supra.
The invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compounds and/or compositions of the invention, including, at least, one or more of the novel COX-2 selective inhibitors, that is optionally nitrosated and/or nitrosylated, and one or more of the NO donors described herein. Associated with such kits can be additional therapeutic agents or compositions (e.g., steroids, NSAIDs, 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists and leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, HMG-CoA inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, thrombin inhibitors, thromboxane inhibitors, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and the like), devices for administering the compositions, and notices in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products which reflects approval by the agency of manufacture, use or sale for humans.